The present invention relates to novel compounds for inhibiting the urokinase plasminogen activator (uPA), which have high bioavailability and oral administerability, and also to the use thereof as therapeutic active compounds for the treatment of urokinase- or/and urokinase receptor-associated disorders such as, for example, tumors and metastasizing. The invention relates in particular to compounds containing hydroxyamidine or hydroxyguanidine groups.
The plasminogen activator of the urokinase type (uPA) plays a key part in tumor invasion and the formation of metastases (Schmitt et al., J. Obst. Gyn. 21 (1995), 151-165). uPA is expressed in many different types of tumor cells (Kwaan, Cancer Metastasis Rev. 11 (1992), 291-311) and binds to the tumor-associated uPA receptor (uPAR) where activation of plasminogen to plasmin occurs. Plasmin is capable of degrading various components of the extracellular matrix (ECM), such as fibronectin, laminin and type IV collagen. It also activates some other ECM-degrading enzymes, in particular matrix metalloproteinases. Large amounts of tumor-associated uPA correlate with a higher risk of metastasizing for cancer patients (Harbeck et al., Cancer Research 62 (2002), 4617-4622). Inhibition of the proteolytic activity of uPA is therefore a good starting point for an antimetastatic therapy.
Some active and selective urokinase inhibitors have been described previously. Thus, EP 1 098 651 discloses benzamidine-type uPA inhibitors, and WO 01/96286 and WO 02/14349 disclose arylguanidine-type uPA inhibitors. A common feature of these synthetic inhibitors is a basic radical consisting of an amidino or/and guanidino group.
However, the known urokinase inhibitors have the disadvantage of being absorbed poorly when applied orally and thus can exert only a low pharmacological action in the body with this type of administration. Pharmaceutical preparations are therefore administered to the patient intravenously usually once, but up to twice weekly over a period of several hours. This puts a great strain on the patient, since this requires considerable time and frequent hospital visits and demands a high level of cooperation of the patient.
Moreover, intravenous administration carries the risk of infections and, especially in the case of paravasally escaping infusate, severe local irritations up to tissue necroses may occur, which require time-consuming subsequent treatments and monitoring.
Intramuscular and subcutaneous routes of administration also do not offer any advantages, since here frequently severe pain at the injection sites and also irritations up to tissue necroses may occur, which likewise require a time-consuming after-treatment.
As discussed above, the amidine- and guanidine-containing urokinase inhibitors exhibit only low pharmacological action when applied orally. A precondition for the therapeutic effect of an active compound is the bioavailability of the latter. Oral administration requires absorption from the gastrointestinal tract. An important mechanism of this kind of membrane penetration is passive diffusion (Gangvar S. et al., DDT (1997) 148-155). The lipophilicity of an active compound was assumed in some parts of the literature to play an important part in passive diffusion via the membrane barriers of the gastrointestinal tract. Thus, EP 0 708 640 describes for pentamidines with antihelminthic action a modification of amidine functions to give amidoxime, amidoxime ester and oxadiazole, with preference being given to using the amidoxime esters and oxadiazole as suitable modifications.
On the other hand, however, it was shown that the degree of lipophilicity alone is not sufficient (Hansch et al., J. Am. Chem. Soc. 86 (1964) 1616-1626) and that an increase in the lipophilicity of the compounds is not an appropriate parameter for predicting membrane penetration. Thus, a direct relation between lipophilicity and membrane. permeation was not found (Conradi et al., Pharm. Res. 9 (1992) 435-439).
The increase in lipophilicity may therefore, in individual cases, increase membrane permeation, but not necessarily lead to an increased oral bioavailability. Thus, in the case of argatroban, conversion of the basic radical to the amidoxime as a prodrug results in improved permeability but, in addition, in the loss of activity (Rewinkel, Adang Cur. Pharm. Design 5 (1999) 1043-1075). It is therefore not readily predictable, whether and which modifications can improve membrane penetration of an active compound in the gastrointestinal tract. It is even less predictable which influence said modifications may have on the pharmaceutical properties of the active compound.